Plant study illuminates brain

Translational medicine is in vogue, the push to solve unmet medical needs through directed research. But science characteristically takes a winding path through basic findings in apparently unrelated research to discoveries with therapeutic implications.

Much of our knowledge about human genetics is derived from work in fruit flies, which on the genetic level and in higher-level features closely resemble people.

A study published June 17 in Neuron illustrates this quirky link. It was performed by a team including scientists from the Salk Institute, Johns Hopkins University, and the University of Western Australia. The scientists themselves come from a mixture of disciplines, such as computational neuroscience, plant science and molecular biology.

The study identifies hitherto unknown differences in three cell types in the mammalian brain by sorting through their epigenomic signatures in the brains of mice. And a key insight about a peculiar kind of methylation in the brains came from studies in Arabidopsis, said co-author Joseph Ecker, a Salk Institute scientist known for his work in Arabidopsis, who has shifted to work in mammals.

The researchers invented a new method of pulling out the epigenomic signals from puréed mouse brains, enabling them to identify rare cell types.

A plant guy like Ecker wouldn't normally be thought of having much to contribute to neuroscience. And plant research at the Salk doesn't grab the public or the media's attention like discoveries in the brain.

But Ecker says his work in non-CG methylation prepared him for what the team found in mice.

Originally, non-CG methylation was postulated to have evolved in plants to control transposons. But when scientists like Ecker started looking at mammalian cells, they found it, while others didn't.

"This flavor of methylation starts at zero and accumulates during the critical period (in brain development)," Ecker said. "We were prepared experimentally to be able to detect it. This is not a new field, looking at methylation. So why wouldn't they have seen it? They didn't have the experimental design to be able to detect it. And if they did see it, they would have thought it was background. And it turns out it's the most abundant kind of methylation in your neurons. So it's not trivial."

The timing of non-CG methylation's increase during brain development coincides with the onset of Rett syndrome, Ecker said, giving researchers insight into why the disease takes time to manifest after birth.

"There's this commonality between epigenetic processes between plants and people," Ecker said.

The Neuron study did more than just detect differences in cell subtypes in the brain, Ecker said. It also linked them with function.

"There's likely to be many many more," Ecker said. "This is just a proof of concept."

Lessons for AI

The findings have implications for artificial intelligence efforts that seek to reverse-engineer consciousness, said Mukamel, who like Sejnowski is also a computational neuroscientist. Models such as neural networks have proven useful, but the artificial neurons don't really simulate what's going on inside the brain. To do that, one has to first identify all the different cell types that affect aspects of consciousness.

"We know that the brain has 80 billion neurons, but most of our computational models treat them like identical units," Mukamel said. "Or maybe there's two kinds, there's excitatory and inhibitory. But biologically speaking, we know they are actually incredibly different from all the others.

"Each one is different not only because of its shape and morphology, the connections it makes to other neurons, but also its intrinsic characteristics, how it responds to inputs. There are neurons that fire a lot of spikes all the time, they're constantly communicating with each other."

The brain requires a balance of activity between all these different types of neurons, especially excitatory and inhibitory neurons, Mukamel said.

"If you have too little inhibition you can have epilepsy, you get positive feedback loops where the activity runs away. If you have too much inhibition you can shut down the cortex and have a coma state."

More subtle gradations, such as schizophrenia are also likely linked to changes in this balance, Mukamel said. But very little is known about the changes in different neural types that cause these conditions.

"In some cases the neurons are very rare," Mukamel said. "In this study we looked at three types of neurons. One is very common, it makes up 80 percent of the neurons in your brain. But one of them is extremely rare. There are likely many cell types yet to be discovered. One of the goals in neuroscience is to catalog and discover all of them."

Other neuronal census grants focus on RNA for this purpose; Ecker's group is the only one devoted to epigenomics.

"We're hoping to combine these different types of data," and get an consensus about the different cell types and what they do, Ecker said.

One of the insights brain epigenomics gives is the history of a cell's development, Ecker said. The epigenomic signatures carry the traces of past patterns of gene regulation.

"We can see events in the epigenome that likely happened much earlier in the developmental program of that cell," Ecker said. "There's a history in the epigenome that I think is one of the cool parts of this study."